title: Schistosomicidal and antifecundity effects of oral treatment of synthetic endoperoxide N-89.
abstract: 1,2,6,7-Tetraoxaspiro[7.11]nonadecane (N-89) is a chemically synthesized compound with good efficacy against malaria parasites. We observed strong anti-schistosomal activities of N-89 both in vitro and in vivo. In a murine model with experimental infection of Schistosoma mansoni, orally administered N-89 at the dose of 300 mg/kg resulted in a significant reduction in worm burden (63%) when mice were treated at 2-weeks postinfection. Strong larvicidal effects of N-89 were confirmed in vitro; schistosomula of S. mansoni were killed by N-89 at an EC50 of 16 nM. In contrast, no significant reduction in worm burden was observed when N-89 was administered at 5 weeks postinfection in vivo. However, egg production was markedly suppressed by N-89 treatment at that time point. On microscopic observation, the intestine of N-89-treated female worms seemed to be empty compared with the control group, and the mean body length was significantly shorter than that of controls. Nutritional impairment in the parasite due to N-89 treatment was possible, and therefore quantification of hemozoin was compared between parasites with or without N-89 treatment. We found that the hemozoin content was significantly reduced in N-89 treated parasites compared with controls (P<0.001). The surface of adult worms was observed by scanning and transmission electron microscopy, but there were no apparent changes. Taken together, these observations suggested that N-89 has strong antischistosomal effects, probably through a unique mode of drug efficacy. As N-89 is less toxic to mammalian host animals, it is a possible drug candidate against schistosomiasis.
authors.affiliation: Section of Environmental Parasitology, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
authors.forename: Toshie
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumagai
authors.forename: Rieko
authors.initials: R
authors.lastname: Shimogawara
authors.forename: Shizuko
authors.initials: S
authors.lastname: Ichinose
authors.forename: Akiko
authors.initials: A
authors.lastname: Hiramoto
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Masayuki
authors.initials: M
authors.lastname: Morita
authors.forename: Masatomo
authors.initials: M
authors.lastname: Nojima
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Wataya
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ohta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D005260:Female; D006420:Hemeproteins / Q000032:analysis / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010270:Parasite Egg Count; D021261:Parasitic Sensitivity Tests; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D012555:Schistosomiasis mansoni / Q000188:drug therapy* / Q000469:parasitology; D012556:Schistosomicides / Q000494:pharmacology* / Q000627:therapeutic use; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C430901:1,2,6,7-tetraoxaspiro(7.11)nonadecane; D006420:Hemeproteins; D006574:Heterocyclic Compounds, 2-Ring; D012556:Schistosomicides; D013141:Spiro Compounds; C020753:hemozoin